Orphan nuclear receptor TLX is expressed in adult mammalian brains and critical in maintaining the proliferative state of neural stem cells. TLX knockout mice display impaired cell proliferation and reduced neural progenitors in neurogenic areas of adult brains. The objective of this study is to identify endogenous TLX ligands in the central nervous system using novel affinity/GC-MS technology and identify synthetic TLX ligands by chemical library screening using cell-based assays. These ligands will be used as tools to study neural stem cell self-renewal and to provide insights into the molecular mechanisms that control neural stem cell proliferation and differentiation. We will also perform preliminary experiments to test the effects of these small molecules on stem cell propagation and neuronal regeneration in neurodegenerative animal models to determine if they are potential pharmacological tools for the improvement of neurodegenerative diseases. Ultimately, these small molecules will be tested as potential therapeutical ligands for the treatment of neurodegenerative diseases such as Alzheimer's disease. These studies will integrate a variety of interdisciplinary approaches and engage full collaborations between two independent groups. Each group will contribute unique yet complementary expertise and resources to the project. Results from these studies will provide unique insights into the nature of TLX ligands and how their functions are related to neural stem cell self-renewal and neurogenesis. Thus, these studies are directly responsive to the NINDS Collaborative Research in Stem Cell Biology. [unreadable] [unreadable] [unreadable]